the neuropsychology of down syndrome: evidence for ... .pdf · the neuropsychology of down...
Post on 13-Jun-2018
Embed Size (px)
The Neuropsychology of down Syndrome: Evidence for Hippocampal DysfunctionAuthor(s): Bruce F. Pennington, Jennifer Moon, Jamie Edgin, Jennifer Stedron, Lynn NadelReviewed work(s):Source: Child Development, Vol. 74, No. 1 (Jan. - Feb., 2003), pp. 75-93Published by: Blackwell Publishing on behalf of the Society for Research in Child DevelopmentStable URL: http://www.jstor.org/stable/3696343 .Accessed: 08/01/2012 00:47
Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at .http://www.jstor.org/page/info/about/policies/terms.jsp
JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range ofcontent in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new formsof scholarship. For more information about JSTOR, please contact email@example.com.
Blackwell Publishing and Society for Research in Child Development are collaborating with JSTOR to digitize,preserve and extend access to Child Development.
Child Development, January/February 2003, Volume 74, Number 1, Pages 75-93
The Neuropsychology of Down Syndrome: Evidence for
Bruce F. Pennington, Jennifer Moon, Jamie Edgin, Jennifer Stedron, and Lynn Nadel
This study tested prefrontal and hippocampal functions in a sample of 28 school-aged (M = 14.7 years, SD = 2.7) individuals with Down syndrome (DS) compared with 28 (M = 4.9 years, SD = .75) typically developing children individually matched on mental age (MA). Both neuropsychological domains were tested with multiple behavioral measures. Benchmark measures of verbal and spatial function demonstrated that this DS sample was similar to others in the literature. The main finding was a significant Group x Domain interaction effect indicating differential hippocampal dysfunction in the group with DS. However, there was a moderate partial correlation (r = .54, controlling for chronological age) between hippocampal and prefrontal composite scores in the DS group, and both composites contributed unique variance to the prediction of MA and adaptive behavior in that group. In sum, these results indicate a particular weakness in hippocampal functions in DS in the context of overall cognitive dysfunction. It is interesting that these results are similar to what has been found in a mouse model of DS. Such a model will make it easier to understand the neurobiological mechanisms that lead to the development of hippocampal dysfunction in DS.
Although Down syndrome (DS) is both the "oldest" and most common genetic mental retardation (MR) syndrome, we know less about its neuropsychology than that of other MR syndromes, such as Fragile X
syndrome (FXS) or Williams syndrome (WS). The
goals of the present study were: (a) to better define the neuropsychological phenotype in DS by testing both prefrontal and hippocampal functions, poten- tial dysfunction of which is suggested by what is known about brain structure in DS; and (b) to test whether this phenotype varies by age.
Understanding the development of the neuro-
psychological phenotypes in MR syndromes has
important implications for theories of cognitive development, because an adequate theory should account for both typical and atypical development. Hence, the pattern of development in MR syn- dromes provides important tests of the universality of the predictions made by such theories, such as
predictions about developmental sequences and the role of various cognitive processes in both develop- mental and individual differences in intelligence (see discussion in Pennington, 2002). In this study, we focused on two cognitive processes, prefrontally mediated executive functions and hippocampally
mediated long-term memory, that are likely to be
important for understanding the development of MR, both in DS specifically and in MR syndromes generally.
DS was first described by Down (1866) well over a
century ago, and its genetic basis-an extra chromo- some 21-was discovered about 40 years ago (LeJeune, Gautier, & Turpin, 1959). DS occurs in 1 in 600 live births and accounts for close to 40% of cases of moderate or worse MR found in the general population. In what follows, we review what is known about genetics, brain development, and
neuropsychology in DS to motivate the present study.
Genetics of DS
Most (about 94%) cases of DS are not familial. Instead, a parent with a normal chromosome number produces an offspring with an extra copy of chromosome 21 (trisomy 21) through a process called nondisjunction, which is failure of one of the
paired chromosomes to separate in meiosis. Non-
disjunction is more likely in mothers, especially older ones, than in fathers, because all of a mother's
eggs are present in an immature form before her birth. In contrast, new sperm are continually being produced by fathers across their reproductive life-
span. The small remainder of cases of DS are familial and reflect either translocation of an extra piece of the long arm of 21 to another chromosome or mosaicism.
Bruce Pennington, Jennifer Moon, Jamie Edgin, and Jennifer Stedron, Department of Psychology, University of Denver; Lynn Nadel, Department of Psychology, University of Arizona.
This research was supported by two grants from NICHD (HD4025 and HD17449).
Correspondence concerning this article should be addressed to Bruce F. Pennington, Department of Psychology, University of Denver, 2155 S. Race St., Denver, CO 80208. Electronic mail may be sent to firstname.lastname@example.org.
? 2003 by the Society for Research in Child Development, Inc. All rights reserved. 0009-3920/2003/7401-0006
76 Pennington et al.
So, the genetic etiology of DS is due to an extra dose of the products of normal genes. Understand-
ing this genetic etiology at the molecular level is a difficult task because it requires that we (a) have identified all the genes on chromosome 21; (b) know which of these are overexpressed, because other
genes or epigenetic interactions may produce dosage compensation for some of the genes on 21; and (c) know which of the overexpressed genes are ex-
pressed early enough in development to cause a
congenital disorder. To understand the etiology of the neurobehavioral phenotype in DS, we need to add a fourth constraint, namely, that the gene is expressed in brain, or at least affects brain
development. Recently, the physical map of chromosome 21 was
completed (Hattori et al., 2000), and it appears that the number of genes is about 225, which is less than the size of the chromosome would predict (e.g., chromosome 22 is smaller than 21 but has about twice as many genes.) A majority of these 225 genes are in the DS region on the long arm of chromosome 21.
Work is now under way to determine which
genes in the DS region meet the other criteria listed earlier to qualify as candidates for the etiology of the neurobehavioral phenotype in DS. Mouse models with trisomies of either single candidate
genes or segments of the DS region have been constructed and are being tested for their neurolo-
gical and neurobehavioral phenotype. Crnic and Pennington (2000) presented a review of this research, including some of the promising candi- date genes that have already been identified. These include the amyloid precursor protein gene (APP), which is also implicated in Alzheimer's disease (AD); a glutamate receptor subunit
gene (GRIK1); the human minibrain homologue (MNB); and neuronal intracellular adhesion mole- cule (DSCAM). Some of these genes are known to have localized effects on brain development. For instance, the APP gene influences the development of the hippocampus (Granholm, Sanders, & Crnic, 2000).
In sum, the genetic etiology of DS is more complicated than that of FXS or WS because it involves many more genes. Recent advances in mapping the human genome and constructing mouse models have accelerated progress toward testing relations between specific genes and specific aspects of the neurobehavioral phenotype in DS. However, it is always possible that trisomy induces developmental instability in a general way and that we will not be able to trace specific phenotypic
features of DS back to extra doses of specific genes (Reeves, Baxter, & Richtsmeir, 2001).
Brain Development in DS
Nadel (1999) recently reviewed what is known about brain development in DS. Broadly speaking, it
appears normal at birth and is invariably abnormal
by adulthood, because virtually all adults with DS have developed some of the neuropathological features of AD disease by around age 35. In addition, by adulthood, the brain is clearly microcephalic, but
differentially greater volume reductions occur in the
hippocampus, prefrontal cortex, and cerebellum (Kesslak, Nagata, Lott, & Nalcioglu, 1994; L6gdberg & Brun, 1993; Raz et al., 1995; Weis, 1991). What is much less clear from the existing data is when these
aspects of abnormal brain development first appear in individuals with DS.
A wide range of studies have found no differences at birth between brains of individuals with and without DS (e.g., Schmidt-Sidor, Wisniewski, She-
pard, & Sersen, 1990). Differences appear in the first few months of life and include delayed myelination, reduced growth of the frontal lobes, a narrowing